9alpha,11alpha-epoxy spirolactones, spirolactols and lactol ethers corresponding

ABSTRACT

9 Alpha ,11 Alpha -Epoxy-4&#39;&#39;,5&#39;&#39;-dihydrospiro(androst-4-ene17,2&#39;&#39;(3&#39;&#39;H)-furan)-3,5&#39;&#39;-dione is converted to the 5 Alpha and 5 Beta isomers of 9 Alpha ,11 Alpha -epoxy-4&#39;&#39;,5&#39;&#39;-dihydrospiro(androstane-17,2&#39;&#39;(3&#39;&#39;H)-furan)-3,5&#39;&#39;-dione and its corresponding lactol and lactol ethers. These compounds are useful as pharmacological agents as demonstrated by their hypotensive and anti-desoxycorticosterone acetate activity.

United States Patent Brown Dec. 17, 1974 9ALPHA,1 IALPHA-EPOXY 3,268,521 8/1966 Pike zoo/239.57 SPIROLACTONES, SPIROLACTOLS AND 3,342,8l3 9/1967 Sarel et al 26()/239.57 3,431,258 3/1969 Lefebure et al. 260/23957 LACTOL ETHERS CORRESPONDING Edward A. Brown, Glenview, lll.

Assignee: G. D. Searle & Co., Chicago, Ill.

Filed: Nov. 19, 1973 Appl. No.: 417,376

Related US. Application Data Continuation-impart of Ser. No. 220,44l, Jan. 24, I972, abandoned.

Inventor:

US. Cl..... 260/239.55 R, 260/239.57, 260/999 Int. Cl. C07c 173/00 Field of Search ../Machine Searched Steroids References Cited UNITED STATES PATENTS 6/1963 Brown 260/239.57

Primary ExaminerHenry A. French Att0rney,.Agent, 0r Firm-John A. Dhucy [57] ABSTRACT 9a,] l ae-Epoxy-4',5 '-dihydrospiro[androst-4-enel7,2'(3H)-furan]-3,5' dione is converted to the 501 and 5B isomers of 9'a,ll'a-epoxy-4,5-dihydrospiro- [androstane-l7,2(3'H)-furan]-3,5'-dione and its corresponding lactol and lactol ethers. These compounds are useful as pharmacological agents as'demonstrated by their hypotensive and anti-desoxycorticosterone acetate activity.

9 Claims, No Drawings 9 ALPHY, l 1 ALPHA-EPOXY SPIROLACTONES,

SPIROLACTOLS AND LACTOL ETHERS CORRESPONDING This application is a continuation-in-part of my copending application Ser. No. 220,411, filed Jan. 24, 1972 now abandoned.

This invention is concerned generally with spirolactones and their derivatives. In particular, it is concerned with 904, Ila-epoxy spirolactones, spirolactols and lactol ethers of the following structural formula wherein Z is a carbonyl radical or a radical of the formula H36 OH WCHzCHzCOOX wherein X is hydrogen, alkali metal, alkaline-earth metal/2 or ammonium.

Preferred alkali metals and alkaline-earth metals encompassed by the X term in formula (lb) include potas sium, sodium, lithium, magnesium and calcium. Those skilled in the art will recognize that the term alkalineearth metal/2" is dictated by the fact that alkalineearth metals are divalent, whereas the other groups represented by X are monovalent; and when, for example, X represents Ca/2 in formula (lb), the contemplated salts are more conventionally depicted thus The instant compounds are prepared conveniently from 9a, lla-epoxy-4,5'-dihydrospiro[androst-4-enel7,2'(3'H)-furan]-3,5-dione, the preparation of that compound being described in US. Pat. No. 3,095,412. Hydrogenation of that starting material in the presence of a suitable catalyst such as a palladium-on-carbon catalyst affords the SB-product of formula (la), namely 9a, 1 la-epoxy-4, 5 -dihydrospiro[SB-androstanel7,2'(3H)-furan]-3,5'dione. Treatment of that compound with methanol and p-toluene-sulfonic acid yields the 3,3-dimethoxy derivative, which is reduced with lithium and ammonia to yield the instant 9a,] laepoxy-4,5-dihydro-5'-hydroxyspiro[SB-androstanel7,2'(3'H)-furan]-3-one. The alkyl ethers of formula (la) then are produced by allowing the latter lactol to react with the appropriate alkanol in the presence of acid. Typically, 901,1 la-epoxy-4,5 '-dihydro-5 hydroxyspiro-[ 5 ,B-androstanel 7,2 3 'H )-furan] -3-one is treated with methanol in the presence of hydrochloric acid to afford 901,1 la-expoxy-4',5-dihydro- 5 -methoxyspiro[ 5 ,B-androstane- 1 7 ,2 3 'H )-furan 3-one.

The Sat-derivatives of formula (la) may be prepared by contacting the aforementioned starting material, 9- 01,1 la-epoxy-4,5 '-dihydrospiro[androst-4-enel7,2'(3H)-furan]-3,5'-dione, with lithium and ammonia to produce 901,1la-epoxy-4,5'-dihydrospiro-[5aandrostane- 1 7,2 3 'H)-furan 1-3 ,5 '-dione a,l la-epoxy-4,5 -dihydro-5 '-hydroxyspiro[ 5aandrostane-l7,2'(3'H)-furan]-3-one. The latter compound can be converted to the corresponding alkyl ethers by the manner described for the SIB-compounds- Reaction of a compound of formula (la) wherein Z is carbonyl with one equivalent of an alkali metal hydroxide affords the corresponding alkali metal salt of formula (lb). This reaction is conveniently conducted in an aqueous medium, preferably in an aqueous alkanol, e.g. methanol. If desired, the resultant salt of formula (lb) can be exposed to a proton source for a short period of time, thus affording the corresponding acid of formula (lb). Thus, subsequent brief contact of an alkali metal salt of formula (lb) with a mineral acid, e.g.

hydrochloric acid, under very dilute conditions, affords The instant compounds exhibit valuable pharmacological, e.g. hypotensive and anti-desoxycorticosterone acetate, activity and thus they are usefulas pharmacological agents. The anti-desoxycorticosterone acetate activity is determined by an assay described in US. Pat. No. 3,412,094 and the hypotensive activity is determined by the following assay.

The test procedure makes use of the fact that chronic administration of desoxycorticosterone acetate induces a self sustaining hypertension that is similar in many respects to essential hypertension in man (D. N. Green et al., American Journal of Physiology, 170, 94, 1952). In this test, SO-g. male Charles River rats are implanted with a 20 mg. wax pellet containing 10 mg. of desoxyand corticosterone acetate. After weeks, their systolic blood pressures are measured electrosphygmographically on the tail artery. The following day, groups of 5 rats are then given 60 mpk. of test compound intragastrically. 4 hours later, the blood pressures are again measured and the decrease in pressure from control day is calculated and compared with concurrent controls. The compound is considered active if it produces a significant decrease in systolic blood pressure.

The invention will appear more fully from the examples which follow. They are not to be construed as limiting either in spirit or in scope as many modifications both in materials and methods will be apparent to one skilled in the art. In the examples which follow, temperatures are given in C. and quantities of material in parts by weight unless parts by volume is specified. The relationship between parts by volume and parts by weight is the same as that existing between milliliters and grams.

EXAMPLE 1 A solution of 3.0 parts of 901,1 la-epoxy-4,5'- dihydrospiro[androst-4-ene-l 7,2 3 'H)-furan]-3,5 dione in 222 parts of tetrahydrofuran is subjected to catalytic hydrogenation with 03 part of 5 percent palladium-on-carbon as catalyst for 5% hours at a hydrogen pressure of 1 atmosphere. After filtration to remove the catalyst and evaporation to remove the solvent. the remaining material is recrystallized from acetone to yield pure 9a,l la-epoxy-4',5 dihydrospiro[SB-androstane-l7,2'(3'l-l)-furan]-3,5- dione. That compound also can be named as 901,1 la epoxyl 7a-hydroxy-3-oxo-5B, l 7a-pregnane-2 l carboxylic acid y-lactone. lt melts at about 247 248 and is structurally represented by the following formula EXAMPLE 2 To a suspension of 2.7 parts of 901,1 la-epoxy-4',5- dihdrospiro[ SB-androstanel 7,2'( 3 'H)-furan]-3,5 dione in 47.5 parts of methanol is added 0.100 part of p-toluenesulfonic acid monohydrate. Stirring the suspension for about 5 minutes produces complete solution, and after 5 hours, 0.5 part of pyridine is added and the solution is transferred into a mixture of ice and water. The precipitate which forms is collected, washed with water and air dried to yield 901,1 la-epoxy-3,3- dimethoxy-4',5'-dihydrospiro[SB-androstanel7,2'(3l-l)-furan]-5'-one, melting at about 95-l00.

EXAMPLE 3 To 200 parts by volume of liquid ammonia is added, with stirring, 0.45 part of lithium wire and then, over a 5 minute period, a solution of 2.7 parts of 9a, 1 laepoxy-3 ,3-dimethoxy-4 ,5 -dihydroxpiro[ 5 B-androstane-l7,2(3'H)-furan]-5'-one in 88.8 parts of tetrahydrofuran. 3 Minutes after the addition is completed, the

solution is decolorized by the addition of 0.6 part of ammonium chloride. After the ammonia has evaporated, 700 parts of water is added. The separated oil is isolated by decantation of the upper aqueous layer and then dissolved in methylene chloride. The methylene chloride solution is washed with water and dried over sodium sulfate. The material which remains after removal of the solvent is dissolved in 7.92 parts of methanol and 1 drop of concentrated hydrochloric acid is added. After 1 hour at room temperature. water is added and the precipitate which forms is collected. That precipitate is dissolved in ethyl acetate, washed with water and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure leaves 901,1 la-epoxy-4',5 '-dihydro-5 methoxyspiro[ Sfi-androstanel 7,2 3 'H )-furan 3-one, as an amorphous solid. That compound is structurally represented by the following formula That compound'is represented by the following structural formula EXAMPLE 4 To 220 parts by volume of liquid ammonia is added 7 with stirring 0.45 part of lithium wire. Then over an 8 minute period, a solution of 3.0 parts of 9a,l lot-epoxy- 4,5 '-dihydrospiro[androst-4-enel 7,2'( 3H)-furan 3,5'-dione in 97.8 parts of tetrahydrofuran is added. 2 Minutes after the addition is completed, the solution is decolorized by the addition of 0.7 part of ammonium chloride. Ammonia is allowed to evaporate for 72 hours and then 700 parts of water is added. The resulting precipitate is recovered by filtration and recrystallized from ethyl acetate to yield pure 9a,] loz-epoxy- 4,5 -dihdro-5 '-hydroxyspiro-[ Sa-androstanel7,2(3H)-furan]-3-one, melting at about l84-189. That compound is structurally represented by the following formula Acidification of the above aqueous filtrate produces a precipitate which is subjected to chromatographic purification on silica gel using chloroform as an eluting solvent. The first peak fraction is recrystallized from ethyl acetate to yield 90:,1 loz-epoxy-4',5- dihydrospiro[ Sa-androstanel 7,2'( 3 'H)-furan]-3,5 dione. That compound, which can also be named as 9- 01,1 la-epoxyl 7-hydroxy-3-oxo-5a, l 7a-pregnane-2 l carboxylic acid y-lactone, is structurally represented by the following formula EXAMPLE 5 An equivalent quantity of ethanol is substituted in the procedure of Example 3, thus producing 901,1 laepoxy-4 ',5 -dihydro-5 '-ethoxyspiro[ SB-androstanel7,2'(3'H)-furan]-3-one.

EXAMPLE 6 EXAMPLE 7 To a solution of 1.0 part of potassium 9a,! lot-epoxyl 7-hydroxy-3-oxo-5a, l 7a-pregnane-2 l -carboxylate in parts of water is added 20 parts of 5 percent hydrochloric acid. The resultant precipitate is filtered off, washed with water and dried in air. The material thus isolated is 904,1 la-epoxyl 7-hydroxy-3-oxo-5a, 1 7apregnane-Z l-carboxylic acid.

EXAMPLE 8 A mixture of 200 parts of 9a,] la-expoxy-l7- hydroxy-3-oxo-5a, l 7a-pregnane-2 l -carboxylic acid. 19 parts of calcium hydroxide and 4,000 parts of 20 percent aqueous methanol is stirred at 40 C. under nitrogen for 2 hours. Solvent is then removed by vacuum distillation and the residue is recrystallized from ethyl acetate. The product thus isolated is calcium bis- [9a,l la-epoxyl 7-hydroxy-3-oxo-5a, 1 7a-pregnane- 2 l-carboxylate EXAMPLE 9 To 20 parts of 2-propanol, saturated with ammonia, is added 1 part of 9a,lla-epoxy-l7-hydroxy-3-oxo- 5a,l7a-pregnane-2lcarboxylic acid. The resulting mixture is allowed to stand at room temperature for 24 hours, at which point solvent is removed by vacuum distillation. The residue is washed with ethyl acetate and dried in air, affording ammonium 901,1 la-epoxyl7-hydroxy-3-oxo-5a,l 7a-pregnane-2 l -carboxylate.

What is claimed is:

7 l. A compound formula wherein Z is selected from the group consisting of carbonyl, hydroxymethylene and (lower alkoxy)methylene radicals and the wavy line represents the a or ,8 configuration.

2. in claim 1, a compound of the formula wherein Z is selected from the group consisting of carbonyl, hydroxymethylene and (lower alkoxy)methylene radicals.

3. As in claim 1, a compound of the formula L Hum) wherein the wavy lines represent the alternative or or ,8 configuration or the epimeric mixture.

5. As in claim 1, the compound which is 9a,! laepoxy-4',5 -dihydrospiro[ SB-androstanel 7,2 3 'H furun]-3,5'-dione.

6. As in claim 1, the, compound which 901,1 la-epoxy 4',5 -dihydro-5 -methoxyspiro[ SB-androstanel7,2'(3'H)-furan]-3-one.

7. As in claim 1, the compound which is 901,110:-

epoxy-4,5 -dihydro-5 '-hydroxyspiro[ SB-androstanel7,2'(3'H)-furan]-3-one.

8. As in claim 1, the compound which is 904,110:- epoxy-4 ,5 '-dihydro-5 '-hydroxyspiro[ 5 a-androstane- 5 l7,2'(3l-l)-furan]-3-one. i

9. As in claim 1, the compound which is 9a,l laepoxy-4',5 '-dihydrospiro[ Sa-androstanel 7,2'-( 3 'H 4. As in claim 1, a compound of the formula I furan] 3,5'-dione.

wherein Z is selected from the group consisting of carbonyl, hydroxymethylene and (lower alkoxy)methylene radicals.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 1 3,855,207

DATED Dec. 17, 197

|N\/ENTOR(S) Edward A. Brown It is certified that error appears in the above-identified patent and that said Letters Patent Q are hereby corrected as shown below:

Column 2, line 29, "ot,lloz" should be 90,llor

Column 5, line 1, should be O Column 8, line l t, "2'( should be 2'( Column 8, line 27, "2'-(" should be 2'( Formula in Claim 1,

H w I H E should read i i O r UNITED STATES PATENT OFFICE Page 2 CERTIFICATE OF CORRECTION PATENTNO. 3,855,207 DATED 1 Dec- 17, 97

INVENTOR(S) Edward A. Brown It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Formula in Claim 2,

should read UNITED STATES PATENT OFFICE Page 3 CERTIFICATE OF CORRECTION PATENT NO. 3,855, 7

DATED Dec. 17, 197

INVENTOR(S) Edward A. Brown It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

should read O: i H

I--- (lower alkoxy) H H3C O: I g

should read (lower alkoxy) Signed and Sealed this fourteenth Of October 1975 [SEAL] Attest:

RUTH C. MASON C. MARSHALL DANN 

1. A COMPOUND FORMULA
 2. As in claim 1, a compound of the formula
 3. As in claim 1, a compound of the formula
 4. As in claim 1, a compound of the formula
 5. As in claim 1, the compound which is 9 Alpha ,11 Alpha -epoxy-4'',5''-dihydrospiro(5 Beta -androstane-17,2''-(3''H)-furan)-3, 5''-dione.
 6. As in claim 1, the compound which 9 Alpha ,11 Alpha -epoxy-4'',5''-dihydro-5''-methoxyspiro(5 Beta -androstane-17,2''(3''H)-furan)-3-one.
 7. As in claim 1, the compound which is 9 Alpha ,11 Alpha -epoxy-4'',5''-dihydro-5''-hydroxyspiro(5 Beta -androstane-17, 2''(3''H)-furan)-3-one.
 8. As in claim 1, the compound which is 9 Alpha ,11 Alpha -epoxy-4'',5''-dihydro-5''-hydroxyspiro(5 Alpha -androstane-17, 2''(3H)-furan)-3-one.
 9. As in claim 1, the compound which is 9 Alpha ,11 Alpha -epoxy-4'',5''-dihydrospiro(5 Alpha -androstane-17,2''-(3''H)-furan)-3,5''-dione. 